Phosphate binder formulation for simple dosing

ABSTRACT

The invention relates to a pharmaceutical composition in the form of pourable granules or a chewable tablet containing at least one phosphate binding substance and at least one effervescent agent. The composition may be taken orally without adding water.

The invention relates to pharmaceutical compositions containingphosphate binders, which may be taken orally without adding water. Thepharmaceutical composition here is preferably in the form of granules ora chewable tablet containing an effervescent agent.

Renally insufficient patients and dialysis patients in particular oftensuffer from a hyperphosphatemia requiring treatment. Hyperphosphatemiais a pathophysiological elevation in the blood phosphate level.Hyperphosphatemia occurs with a massive intake of phosphate, massiverelease of phosphate due to tissue destruction, reduced phosphateelimination in advanced renal failure and/or conditions with anincreased phosphate resorption through the kidneys. The rise in serumphosphate may lead to deposition of calcium phosphate in blood vesselsand other tissues. Chronic hyperphosphatemia can lead to calcificationof tissues and blood vessels, which may result in circulation disorders,myocardial infarction and/or a stroke. Therefore renally insufficientpatients must usually take phosphate binders to control their serumphosphate levels. The phosphate binders should be taken with meals tobind the phosphate contained in food in the form of sparingly solublesalts or unabsorbable complexes in the intestine and therefore eliminatethem with the feces. To do so, the patients must take a large quantityof the phosphate binder, usually in the form of a large number oftablets, for example, 1 to 5 tablets three times daily with each meal.To be able to take large quantities more easily or with fewer tablets,it is either necessary to take an even larger number of tablets in thecase of smaller tablets or much larger tablets that are more difficultto take may be administered in the case of fewer tablets. However, thislarge number of tablets is only a portion of the total oral medicationtaken by a renally insufficient patient. In a recent study on 233dialysis patients, they were taking an average of 11 differentmedications, resulting in 19 tablets to be taken per day as the median(Chiu, Y. W. 2009). Of these, approximately 50% were phosphate binders.

In addition, renally insufficient patients and in particular dialysispatients are allowed to drink only a small amount of water per day, sothat the tablets cannot be swallowed easily. Renally insufficientpatients cannot eliminate excess fluid from the body via the urine orcan do so only to a limited extent. Therefore, most renally insufficientpatients suffer from a permanent fluid excess in the body which has anegative influence on their well-being as well as their mortality.Excess fluid can cause hypertension, which can damage the cardiovascularsystem and in particular the function of the left ventricle and thus cancontribute indirectly toward an increased mortality of renallyinsufficient patients due to cardiovascular diseases. Furthermore, alarge percentage of renally insufficient patients suffer from anemia andreceive hematopoietic medication in the form of Epogen or analogs and inthe form of iron preparations. A fluid excess reduces the concentrationof the hematopoietic medications and thus makes suitable dosing of thesemedications much more difficult. Therefore, control of fluid intake isextremely important in renally insufficient patients. In most cases, thegoal is to minimize fluid intake in renally insufficient patients.

This is complicated by the fact that dialysis patients haveapproximately half as much saliva as healthy control groups (Bayraktar,G., 2004). Compliance in taking medication is therefore influenced in anegative sense. In contrast with the number of different medicationsprescribed, the number of phosphate binder tablets prescribed must beseen in conjunction with patient compliance in particular (Arnas, M. D.,2010). If dialysis patients are asked which medication they would mostprefer to omit if they had a choice, phosphate binders would be listedin first place (Arenas, M. D. 2010). An improved dosage form that ispatient friendly and better-tasting phosphate binders would make asignificant contribution toward meeting patients' requests (Lindberg,M., 2008).

U.S. Pat. No. 7,465,465 discloses chewable tablets with lanthanum as aphosphate binder which must be chewed before swallowing to remedy theseproblems. This may be difficult for a dialysis patient who has reducedsaliva. Crushing the tablet and then distributing it on food or a spoonis associated with the risk of taking too little of the activeingredient because of losses in preparation and/or incomplete ingestionof the foodstuff.

EP 1 924 246 discloses powder preparations with a suspension stabilizerfor taking the powder after suspending it in water. This is associatedwith the disadvantage of the larger quantity of water of the suspensionagainst the water restrictions for dialysis patients. It is customary tosuspend such a powder in at least 40 mL-60 mL water before it is taken.Thus the total quantity of water ingested adds up to approximately120-300 mL per day for administration of the phosphate binder alone. Tosupply the total dose of the phosphate binder more reliably, it is alsonecessary to use more water to rinse off the powder particles adheringto the edge, which remain on the glass wall after taking the suspensionand then to also drink this water.

To reduce the water ingested with the phosphate binder, WO 2008/011126discloses concentrated solutions of calcium acetate with largequantities of polyols, sweeteners and taste-masking substances. In suchformulations, a portion of the bad inherent taste of calcium phosphateremains perceptible overall on the one hand, and on the other hand, anumber of patients reject the intense, always uniform taste of thesweeteners and flavorings, which do not correspond to all meals. Forcombination products with readily water-soluble calcium acetate andsparingly soluble magnesium carbonate, there is the additionaldisadvantage of dosing inaccuracy because it is difficult to dosemagnesium in suspended form by means of a dropper, etc.

All the approaches toward simpler dosing described here have theadditional disadvantage that in any case the product is distributedinvoluntarily in wide areas of the oral cavity, producing an unwantedtaste. This taste becomes more intense when parts of the product remainin parts of the oral cavity for an even longer period of time.

Therefore, the object of the invention is to make available a dosageform for phosphate binders that will allow renally insufficient patientsto easily take the required large quantities of phosphate binderswithout any additional quantities of water. In a second aspect, thedosage forms should mask any poor taste of the phosphate binder andshould impart a pleasant feel in the mouth. In another aspect the objectof the invention is to make available a composition which will bedistributed involuntarily in the oral cavity as little as possible andwill allow accurate doing.

These objects are achieved through the composition according to Claim 1and its application as well as through the subject matters of theadditional independent claims.

Additional objects are achieved by preferred embodiments of theinvention which are the subject matter of the dependent claims.

A pharmaceutical composition in the form of pourable granules or achewable tablet containing at least one phosphate binding substance andat least one effervescent agent which in turn contains an alkalicarbonate or an alkaline earth carbonate or an alkali bicarbonate oralkaline earth bicarbonate and a solid organic edible acid or the acidsalt thereof is used in the treatment of renally insufficient patientsand is characterized in that the granules are administered orallywithout adding water or another liquid and can then be swallowed. Inthis way, the medication can be taken without any additional intake offluid. Washing it down with water is not absolutely ruled out but is notnecessary. It is decisive that the composition is taken first in themouth without water. The effervescent agent has the effect of maskingthe taste and imparts a pleasant feeling in the mouth. In this way, thepharmaceutical composition can be partially dissolved in saliva andswallowed mostly completely by the tongue.

The pharmaceutical composition is ideally administered from a stickpackdirectly to the tongue. In the case of an active ingredient with a badtaste, it may additionally be coated in the granules to mask the tasteif a simple flavoring and/or the effervescent agent is not sufficient tomask the taste.

Phosphate binders are substances which interact with phosphate ionsincluding crotonated phosphate ions and thereby hinder them in beingtaken up from the gastrointestinal tract into the blood stream and thusinto the body to ensure the elimination of phosphates in the feces.

Phosphate binders that may be used include in particular calcium,magnesium, aluminum, iron, lanthanum and bismuth salts, whose solubilityproducts are larger than those of the corresponding phosphate salts ofthese cations. In addition, phosphate-binding organic polymers having ananion exchanger function such as sevelamer, AMG 223 (Amgen) and MCI-196(Colestilan, Mitsubishi) are suitable substances for the invention.Suitable aluminum salts include all the pharmaceutically tolerable saltswhich fulfill the above requirements, especially preferably oxides, inparticular algedrate and/or hydroxides. All the pharmaceuticallyacceptable salts which fulfill the above requirements, in particularlanthanum carbonate including its hydrates are suitable as the lanthanumsalts. All the pharmaceutically acceptable salts which fulfill the aboverequirements, preferably chlorides, sulfates, hydroxides, oxides,carbonates and in particular heavy magnesium carbonate are suitable asthe magnesium salts. Preferred phosphate binders based on metal saltsinclude iron hydroxides, iron oxide hydroxides and iron citrates, inparticular iron preparations, which are stabilized by carbohydrates orhumic acid or are bound to them or form sheet salts with magnesium, forexample, fermagates and calcium salts, preferably calcium carbonateand/or calcium chloride and especially preferably calcium acetate.Calcium acetate is preferred in comparison with calcium carbonatebecause of its high solubility but it has the disadvantage of anextremely unpleasant taste. Of the metal salts, calcium salts areespecially good phosphate binders and have a favorable price. However,as a disadvantage it is discussed that calcium preparations can causehypercalcemia in many patients, i.e., elevated blood calcium levels.Chronic hypercalcemia is associated with the risk of calcification ofthe blood vessels and thus in turn with the risk of cardiovasculardiseases. Replacing some of the calcium in such phosphate binders withmagnesium which itself functions as a phosphate binder reduces the riskof development of hypercalcemia. It has been demonstrated that by addingmagnesium salts, in particular magnesium carbonate to phosphate bindingcalcium acetate, hypercalcemia and therefore calcification can belargely prevented and no negative effects can be detected in comparisonwith patients treated with calcium-free phosphate binders (de Francisco,A. L. M. et al., Nephrol Dial Transplant 2010). To achieve this effect,a preferred weight ratio of calcium acetate to magnesium carbonate of1:1 to 4:1 is assumed, but a ratio of 1.2:1 to 3:1 is especiallypreferred and a ratio of 1.5:1 to 2:1 is most especially preferred.Magnesium salts also have an independent phosphate binding effect, sothat in the presence of magnesium salts, the quantity of phosphatebinder based on calcium required can be reduced. A combination ofcalcium acetate and magnesium carbonate thus constitutes an especiallypreferred composition in the sense of the present invention. Anotherspecial advantage of this combination is derived from the fact thatmagnesium carbonate is also a preferred ingredient of the effervescentagent inasmuch as magnesium carbonate can fulfill two functions at thesame time within the composition. The weight and the volume of thecomposition per dose to be taken by the patient are further reduced inthis way. A daily dose ideally contains 100 mg to 3000 mg calcium and 0mg to 1500 mg magnesium abased on the weight of the metal ions, but 300mg to 1800 mg calcium is preferred and 180 mg to 750 mg magnesium,450-1350 mg calcium and 180-540 mg, magnesium being most preferred. Inthe absence of magnesium, the preferred quantities for calcium areincreased by a factor of 1.5.

For ion exchange polymers, in particular sevelamer, the ideal daily doseis 500-12,000 mg preferably 2000-10,000 mg and especially preferably5000-8000 mg.

For phosphate binders based on lanthanum, the ideal daily dose based onlanthanum is 250-5000 mg preferably 750-4000 mg, 1500-3000 mg.

The daily dose is usually divided among 3 to 15 individual doses to betaken with each meal. It is customary to take 1 to 4 individual doseswith the three main meals per day.

Because of the large quantity in which phosphate binders must still betaken, one goal of the present invention is to minimize the weight andthe volume of the final composition. The admixture of other excipientsshould be limited to a minimum. The composition according to theinvention preferably contains 15% to 80% of the phosphate binding activeingredient, especially preferably 20% to 70% and most especiallypreferably 25% to 60%.

All the aforementioned phosphate binders must be taken in largequantities and the object of the present invention is to make itpossible for these quantities to be taken without additional intake offluid. Tablets of this size or capsules containing the active ingredientare virtually impossible to swallow without taking some fluid at thesame time. The only remaining options are a chewable tablet or granules.For both dosage forms it is of crucial importance for the dosage form totaste good and to impart a pleasant feeling in the mouth because bothdosage forms have a large surface area in the mouth when taken and havethe potential to distribute themselves throughout the entire mouth. Anunpleasant taste or an unpleasant feeling in the mouth is thus perceivedespecially strongly with these dosage forms. All the aforementionedphosphate binders in the form of granules or a chewable tablet thatdisintegrates in the mouth impart an unpleasant “chalky” or “sandy”feeling in the mouth and in particular impart a dry feeling. The dryfeeling in the mouth is further exacerbated in renally insufficientpatients who often suffer from a lack of saliva. Furthermore, some ofthe active ingredients, for example, calcium acetate have a veryunpleasant inherent taste.

According to the invention, an effervescent agent is therefore added tothe composition. The effervescent agent is dissolved by saliva in themouth, thereby releasing carbon dioxide in a chemical acid-basereaction. The carbon dioxide thereby released stimulates additionalformation of saliva, especially in cooperation with flavorings and isalso perceived as fresh and pleasant in the mouth. Due to the increasedsalivation, the feeling of dryness disappears and the composition can beswallowed more easily after being mixed with saliva. In addition, thecarbon dioxide thereby released has a taste-masking effect per se.

The effervescent agent contains at least one solid organic edible acidand/or its salt and at least one salt which released carbon dioxide, inparticular a carbonate, preferably selected from the group of alkalisalts and alkaline earth salts and their metal hydrogen salts.Especially suitable are sodium carbonate, sodium bicarbonate, potassiumcarbonate, potassium bicarbonate, magnesium carbonate and/or calciumcarbonate. Magnesium carbonate is especially preferred because inaddition to the effervescent function it also acts as an activeingredient against hypercalcemia and has phosphate binding properties.Calcium carbonate is also preferably used because the calcium suppliedin the effervescent agent has a phosphate-binding effect and thus makesit possible to reduce the amount of active ingredient. The effervescentreaction also counteracts the disadvantage of the low solubility ofcalcium carbonate. Suitable acids include in particular citric acid,tartaric acid, malic acid, adipic acid, succinic acid, fumaric acid,ascorbic acid, maleic acid and ascorbic acid as well as partial salts ofthese acids in the case of polybasic acids, for example, monosodiumtartrate. Such acids, which additionally stimulate salivation and/orhave a pleasant inherent taste, are also especially preferred tofacilitate swallowing of the slightly foaming preparation and also toimprove the taste of the composition. Tartaric acid, citric acid,ascorbic acid, sodium and potassium tartrate, sodium hydrogen citrateand sodium ascorbate are especially suitable for this purpose.

The effervescent formulations according to the invention may be producedby conventional methods that are known in the state of the art. Forexample, the acids and carbonates are granulated separately, preferablyby moist granulation, during which the active ingredients are added toone of the granules. After mixing, soluble lubricants such as sodiumbenzoate or polyethylene glycols are added to the carefully driedgranulates and compressed. According to another method, all acids,carbonates and active ingredients are mixed together and heated in areactor until the citric acid releases its water of crystallization, forexample, and granules are formed. Repeated stirring is necessary toobtain a uniform composition, which is then screened rapidly and driedcarefully. Good drying is absolutely essential to avoid gradualdisintegration of the granules due to reaction of the acids with thecarbonates. To achieve rapid drying, for example, vacuum drying cabinetsor so-called one-pot granulators with vacuum-assisted drying are used.In another variant of production, the initial reaction of the acid withbasic components and subsequent drying takes place in a vacuum. Theresulting effervescent granules according to the invention are pressedwith additional ingredients of the composition to form chewable tabletsor are packed into stickpacks. The dosage of the effervescentformulation plays an important role for the invention. On the one handenough effervescent agent must be present to permit a perceptiblerelease of carbon dioxide which produces the pleasantly fresh feeling inthe mouth and masks the taste. On the other hand the composition shouldnot foam too much in the mouth because most patients do not perceivethis as pleasant. The proportion of effervescent agent in thecomposition is therefore ideally 3-60% of the total weight, preferably5-45% and especially preferably 10-30%.

There are various methods with which those skilled in the art arefamiliar which make it possible to incorporate phosphate binding activeingredients into granules. The active ingredient here, optionally withthe addition of excipients, is preferably itself in the form of granuleswhich represent the final granulated composition or are a componentthereof. On incorporation into granules, both pregranulated activeingredients and powdered active ingredients which are then granulated insubsequent steps may be used. The dosage forms may contain excipientswhich are bound into the granular structure as well as being added inthe form of a powder to the particles of granules. The excipients usedmay include in particular fillers, sweeteners, acidifying agents,flavorings, coating agents, flow regulating agents and partingcompounds. Granulation methods that may be used include in particularmoist granulation, dry granulation and melt granulation, although othermethods are not ruled out. In moist granulation, aqueous methods arepreferred for environmental reasons and for reasons of occupationalsafety, but methods using organic solvents are also possible. For moistgranulation and melt granulation, fluidized bed methods and high speedmixer methods are preferred (e.g., Diosna mixer or Granumat from Bohle)but alternative methods are also possible. Granulation methods whichyield the densest possible granules to reduce the volume of the dosetaken are preferred. In addition granules having a smooth surface withlittle porosity, which permit uniform moistening by saliva and impart apleasant feeling in the mouth due to their smoothness are alsopreferred. Preferred granulation methods include moist granulation ofthe active ingredients with binders and subsequent drying in a fluidizedbed and melt granulation.

In preferred embodiments, additional advantageous excipients are addedto the active ingredient in granulation. Various excipients—such asfillers, parting compounds, binders, disintegrants, flow regulators,sweeteners and/or flavorings—are used for technical and pharmaceuticalreasons in granulation and are very familiar to those skilled in theart. However, within the scope of the present invention, the excipientsalso ideally contribute toward improving the feeling in the mouth andthe taste of the granules.

The fillers may be all pharmaceutically conventional tablet and granularfillers in particular inert compounds such as celluloses, starchesand/or lactose. Sugars such as sucrose, glucose or fructose whichimprove the taste of the formulation and thus function as sweeteners atthe same time are preferred within the scope of this invention. Sugaralcohols are especially preferred because they mask the unpleasant tasteof the active ingredients with a pleasantly sweet inherent taste whileon the other hand being easy to moisten with saliva. This leads to thedesired effect of increased salivation and contributes toward a pleasantcool feeling in the mouth. Within the scope of the present invention,sugar alcohols may preferably be selected from the group comprisingmannitol, inositol, erythritol, lactitol, xylitol, maltitol, malbitol,sorbitol, inulin and isomalt.

The sugar alcohols mentioned above may also be used as preferred bindersin melt granulation. Other preferred binders within the scope of theinvention in granulation with taste-masking properties at the same timeinclude: cyclodextrin, alginic acid, Eudragit E-100, polacrilin,microcrystalline cellulose, beeswax, glycerol esters, triglycerides,polyglycerol esters of long-chain fatty acids, PEG, fatty alcohol PEGesters, fatty alcohol PEG ethers, PVP and derivatives, polyacrylic acid,polyacrylates, polymethacrylates and any combinations thereof.Low-melting binders which allow granulation at low temperatures andbinders which are simultaneously hydrophilic or even to form hydrogelsare especially preferred because they impart a better feeling in themouth.

Sweeteners, e.g., aspartame, saccharine, cyclamate, acesulfam,neohesperidine, trehalose, alitame, dihydrochalcone, thaumatin andsucralose may also be used for additional sweetening because thesesweeteners can also stimulate salivation in addition to having asweetening effect.

In addition to a simple sweetening, flavorings and taste-improvingsubstances are used to mask the taste, to produce a pleasant taste andto increase salivation. Fruit aromas and especially preferably citrusfruit aromas are preferred here because these impart an especially freshtaste and a cool feeling in the mouth. For the same reasons, mintflavorings are also preferred.

Flow regulators that may be used include those substances which allow aneasy and uniform flow of the granules such as in particular highlydisperse silicon dioxide, precipitated silicon dioxide and talc.

Fatty acids and their salts, e.g., stearic acid, magnesium stearate,calcium stearate, behenic acid and calcium behenate, fatty alcohols,e.g., stearyl alcohol, fats, e.g., hardened triglycerides and hardenedcastor oil, sodium fumaryl stearate, polyethylene glycol with amolecular weight of >1500 Dalton as well as talc are suitable partingcompounds.

In another preferred embodiment, the active ingredient granules arecoated with a substance to mask the taste. Those skilled in the art arefamiliar with many coatings and coating methods for taste-maskingcoatings. For example, the following materials are suitable fortaste-masking coatings in the sense of this invention:

Cellulose acetate or cellulose acetate butyrate with PVP, Eudragit RD100 with carboxymethyl cellulose, polyvinyl alcohol and polyethyleneglycol copolymer, Eudragit 100 and PVP, polyvinyl acetate andpharmaceutically acceptable hydrophilic polymers, Eudragit E100 andpharmaceutically acceptable acids, polyacrylates, polymethacrylates,polymethacrylic esters, combinations of enteric polymers withhydrophilic gel-forming polymers such as polyvinyl acetate orpolyvinylpyrrolidone (PVP).

The preferred coating method is spray coating in a fluidized bed. Inprinciple, both top spray and bottom spray methods are customary here.The bottom spray method is preferred here for coating particles andgranules thereof. Typical representatives of devices in this fieldinclude those available from the following companies: Glatt, Aeromatic,Diosna and Bohle. A so-called Wurster insert is preferred for the bottomspray method. Another preferred type of bottom spray fluidized coatingdevice is the ball coater and/or those from the Mycrolab, Unilab,Pilotlab family and/or HDGC from the company Oyster Hüttlin. As thoseskilled in the art are aware, in all these systems the coating isperformed by spraying a solution of suspension of a polymer in waterand/or another organic solvent is applied by means of a nozzle to afluidized bed of particles and/or granules or pellets, where thefluidized bed is produced by introducing air, usually heated, and thendrying.

In addition to traditional methods in which the coating is dissolved inwater or an organic solvent and then dried in a fluidized bed, the meltcoating method is considered and is especially preferred. In the meltcoating method, low melting binders are used, additional substancesbeing dissolved or suspended in their melt. The melt is sprayed in thefluidized bed and the coating hardens on cooling. Ideally binders whichthemselves have a taste-masking effect and cause a pleasant perceptionin the mouth are used, for example, lipophilic substances selected fromthe group of lipids, waxes, glycerol esters, triglycerides, polyglycerolesters of long-chain fatty acids, PEG, fatty alcohol PEG esters, fattyalcohol PEG ethers and PVP and derivatives, polyacrylic acids andpolyacrylates, polymethacrylates and combinations thereof. Low-meltingbinders which allow granulation at low temperatures and binders whichare hydrophilic at the same time or even tend to form hydrogels areespecially preferred because this imparts a better feeling in the mouth.

A surface modifier which produces a smooth surface that is easy tomoisten and thus additionally improves the feeling in the mouth ispreferably added to the coating. Examples of surface modifiers includesorbitan fatty acid esters, polyoxyethylalkyl esters, polyoxyethylalkylethers, polyoxyethyl sorbitan fatty acid esters, polyoxyethyl stearatesand copolymers thereof.

If a taste-masking coating is used within the scope of the presentinvention, then the effervescent agent should essentially not be presentin the active ingredient granules because the taste-masking coatingwould prevent moistening of the effervescent agent by saliva on the onehand and would thus delay the release of carbon dioxide while on theother hand any carbon dioxide that might be formed could at leastpartially break open the taste-masking coating. In such a case theeffervescent agent may be added in the form of additional granules or asa powder to the composition. In another embodiment, the effervescentagent may be present in the outer layer of the coating. This may be thesame layer as the taste-masking coating or an additional layer.

The same thing also applies to sweeteners and flavorings which cannotmanifest their taste-improving properties in the core of the coatedactive ingredient granules as for the effervescent agent. Sweeteners andflavorings are also preferably added in the form of additional granulesor as a powder, where these may be the granules containing theeffervescent agent or they may especially preferably be part of an outercoating.

The composition may be supplied in the form of free-flowing granules ora chewable tablet. The chewable tablet offers the advantages of ease ofadministration and accurate doseability as a tablet. Nevertheless withinthe scope of the invention, the pourable granular form is preferred. Onereason for this is that the chewable tablet must be chewed. Thereforetaste-masking coatings, for one thing, may be destroyed and for anotherthing chewing produces a large volume distribution in the mouth and mayresult in the substance sticking to the teeth, which makes rapid andcomplete swallowing difficult. The granules may be applied directly tothe tongue and dissolved there, resulting in a comparatively minordistribution of the particles in the mouth between the tongue and gumsand the granules can be swallowed completely. Within the scope of theinvention, it has been found that particles with an average particlesize of 100-3500 μm preferably 250-2500 μm and especially preferably400-2000 μm are perceived as being especially pleasant for thisapplication. (The average particle size can be determined by the shakingscreen method according to DIN 53477.) Particles of this size are oftencombined in the mouth to form a particularly pasty consistency which iseasy to swallow. Larger particles prevent this advantageous pastyconsistency from being formed whereas smaller particles in the mouth areperceived as dusty. Smaller particles because of their larger totalsurface area adsorb more saliva so more saliva is needed for initialdissolving, which promotes the unwanted effect of dryness in the mouth.

The phosphate binder in a daily total dose of 40-10,000 mg may bepackaged as a single dose or as multiple doses. The daily dose should bedivided among meals, usually three, and taken with meals. The precisedosing is preferably adjusted according to the patient's phosphatelevels in the course of treatment. It is thus advisable to package themost common dose per meal in individual packages. Patients having a lowdemand for phosphate binders would then take less than the totalcontents of one package per meal or would divide the contents of onepackage among several meals. Patients having a high demand could takemore than the contents of one package.

For a phosphate binder based on calcium, preferably 70-700 mg calciumand 0-300 mg magnesium, based on the weight of the metal ions,preferably 100-450 mg calcium and 50-240 mg magnesium and mostespecially preferably 150-300 mg and 80-160 mg magnesium are packagedindividually.

For a phosphate binder based on an ion exchanger, preferably 150-3000 mgof the active ingredient, preferably 300-2500 mg and most especiallypreferably 600-1700 mg are packaged individually.

For a phosphate binder based on lanthanum, preferably 40-1000 mglanthanum, based on the weight of the metal ions, preferably 50-750 mgand most especially preferably 80-500 mg is packaged individually.

Suitable packages for the preparations according to the invention in theform of granules include in particular packages containing the dose ofphosphate binder to be administered and from which the preparation canbe applied directly to the mouth, preferably to the tongue. A bagpackage, especially preferably a so-called stickpack package in whichthe preparation is enclosed in a tubular package, is preferred. Thetubular package is preferably produced by placing the material,preferably a film, around a round guide sleeve and connecting it at thesides of the material that come in contact. The resulting tube is sealedat its lower end, filled with the preparation which is then preferablydosed through the guide sleeve and then sealed at its upper end. In thecase of a film tube, the welding of the upper part of the packagepreferably takes place together with the welding of the lower part ofthe following package and the separation of the two packages. Afterbeing cut or torn open on a short side of the bag, the stickpack has asmall opening of preferably less than 1 cm diameter out of which thepreparation can be administered into the mouth out of the bag,preferably following gravity. The granules pour out of the package intothe mouth and the granules may be supplied in portions in the case oflarger filling quantities in the bag. Smaller filling quantities may beadministered all at once as a bulk dose.

The filling quantity of a stickpack is based on the quantity whichcontains an adequate amount of the active ingredient on the one hand andon the other hand the quantity that is still perceived as pleasant bythe patient when taking it in the mouth. Such a stickpack thereforepreferably contains 0.5-8 g of the total composition; especiallypreferably the stickpack contains 0.75-5 g of the composition, and mostespecially preferably 1-3.5 g.

EXAMPLES Example 1

A granular preparation containing 110 mg calcium and 60 mg magnesium perdose can be prepared by the following method:

Calcium acetate (according to the 435 g  requirements of the EuropeanPharmacopoeia)* Heavy magnesium carbonate (according to the 235 g requirements of the European Pharmacopoeia) Mannitol 338 g  Sodiumbicarbonate 67 g Monosodium dihydrogen citrate 67 g Citric acid 13 gAspartame  5 g Orange flavoring 30 g Highly-disperse silicon dioxide 10g *For anhydrous calcium acetate, for hydrated calcium acetate, theinitial weight must be adjusted, based on the water content and morecalcium acetate must be added. This step must be taken into account forall examples using calcium acetate.

Calcium acetate, heavy magnesium carbonate, sodium hydrogen phosphateand 750 of the mannitol are converted to granules by roller compactingand subsequent screening for a 1.5 mm screen.

Monosodium hydrogen citrate, citric acid and the remaining 25% of themannitol are also converted to granules by means of roller compactingand then screening through a 1.5 mm screen.

Granules, aspartame, orange flavoring and highly disperse silicondioxide are mixed in a container mixer and then packaged in stickpackswith a filling weight of 1200 mg each.

Example 2

A granular preparation with 110 mg calcium and 60 mg magnesium per dosecan also be prepared by the following method:

Effervescent granules:

Citric acid 75 g Monosodium citrate 75 g Sodium bicarbonate 150 g Sodium cyclamate 20 g Sucrose palmitate  2 g Hydroxypropylmethylcellulose  5 g

Other ingredients:

Calcium acetate (according to the 435 g requirements of the EuropeanPharmacopoeia), granulated (Paul Lohmann) Heavy magnesium carbonate(according to the 262 g requirements of the European Pharmacopoeia),granulated with approximately 10% cornstarch (magnesium carbonate DC90S/C Paul Lohmann) Aspartame  10 g Sorbitol 200 g Xylitol 136 g Orangeflavoring  30 g

For the effervescent granules, citric acid, monosodium citrate, sodiumbicarbonate, sodium cyclamate, sucrose palmitate and hydroxypropylcellulose are mixed in a Diosna mixer with a 1-liter container andsprayed slowly with 5 g ethanol through a nozzle while stirring. Nextgranulation is continued for 10 minutes. Then the composition is spreadon a metal sheet and dried for 60 minutes in a vacuum drying cabinet at30° C. and a final pressure of <50 mbar.

The resulting effervescent granules are pressed through a 1 mm screenand mixed with the other ingredients in a 5-liter cube mixer.

The mixture is welded into an aluminum stickpack in portions of 1400 mg.

Example 3

A granular preparation with 167 mg calcium per dose can be prepared bythe following method:

Calcium acetate (according to the 660 g requirements of the EuropeanPharmacopoeia), granulated (Paul Lohmann) Aspartame  10 g Sorbitol 200 gXylitol 100 g Orange flavoring  30 g Finished effervescent granules fromExample 2 200 g

All the ingredients are mixed in a 5-liter cube mixer. The mixture iswelded into an aluminum stickpack in portions of 1200 mg each.

Example 4

A granular preparation with 167 mg calcium per dose can also be preparedby the following method:

Calcium acetate with a taste-masking coating:

Calcium acetate (according to the 1980 g requirements of the EuropeanPharmacopoeia), granulated (Paul Lohmann) Glycerol palmitostearate(Precirol ® ATO 5,  220 g Gattefosse)

Other ingredients:

Aspartame  30 g Sorbitol 600 g Xylitol 320 g Orange flavoring 100 gFinished effervescent granules 650 g from Example 2

The calcium acetate is moved in a fluidized bed apparatus (Unilab 05from Hüttlin) at an inlet air temperature of 35° C. and coated at aspray rate of 6 g/min with a melt of glycerol palmitostearate heated to80° C. and atomized through a spray nozzle of 1 mm at an atmosphericpressure of 1 bar by means of spray air heated to 60° C. Then the coatedgranulates are cooled to 25° C. for 10 minutes in the ball coater.

The coated calcium acetate is passed through a 2 mm screen, mixed withthe other ingredients in a 10-liter cube mixer and then welded inaluminum stickpacks in portions of 1300 mg each.

Example 5

A granular preparation with 220 mg calcium and 120 mg magnesium per dosecan be prepared by the following method:

Calcium acetate from Example 4 with a taste- 1450 g  masking coating(calcium acetate content 90%) Heavy magnesium carbonate (according tothe 785 g requirements of the European Pharmacopoeia), granulated withapproximately 10% cornstarch (magnesium carbonate DC90 S/C Paul Lohmann)Aspartame  30 g Sorbitol 600 g Xylitol 400 g Orange flavoring 100 gFinished effervescent granules from Example 2 625 g

All the ingredients are mixed in a 10-liter cube mixer and welded intoaluminum stickpacks in portions of 2660 mg each.

Example 6

A granular preparation with 220 mg calcium and 120 mg magnesium per dosecan be prepared by the following method:

Calcium acetate from Example 4 with a taste- 1450 g  masking coating(calcium acetate content 90%) Heavy magnesium carbonate (according tothe 785 g requirements of the European Pharmacopoeia), granulated withapproximately 10% cornstarch (magnesium carbonate DC90 S/C Paul Lohmann)Aspartame  30 g Sorbitol 550 g Xylitol 400 g Sodium carboxymethylcellulose  50 g Orange flavoring 100 g Finished effervescent granulesfrom Example 2 625 g

All the ingredients are mixed in a 10-liter cube mixer and welded intoaluminum stickpacks in portions of 2660 mg.

Example 7

The finished mixture from Example 4 can be filled into stickpacks of acorresponding filling volume (adaptable through the width and especiallythe length of the stickpacks) in the following portions to preparedifferent calcium doses:

Corresponding weight of calcium acetate Filling amount of Calcium dose(anhydrous) stickpacks  50 mg 198 mg  389 mg 100 mg 395 mg  778 mg 150mg 593 mg 1168 mg 200 mg 791 mg 1557 mg 250 mg 988 mg 1946 mg 300 mg1186 mg  2335 mg 350 mg 1384 mg  2725 mg 400 mg 1582 mg  3114 mg 500 mg1977 mg  3892 mg

Example 8

A granular preparation with 220 mg calcium and 110 mg magnesium per dosecan be prepared by the following method:

Calcium acetate from Example 4 with a taste- 1450 g  masking coating(calcium acetate content 90%) Heavy magnesium carbonate (according tothe 720 g requirements of the European Pharmacopoeia), granulated withapproximately 10% cornstarch (magnesium carbonate DC90 S/C Paul Lohmann)Aspartame  30 g Sorbitol 550 g Xylitol 375 g Sodium carboxymethylcellulose  50 g Orange flavoring 100 g Finished effervescent granulesfrom Example 2 625 g

All the ingredients are mixed in a 10-liter cube mixer and welded intoaluminum stickpacks in portions of 2600 mg each.

Example 9

The finished mixture from Example 8 can be filled into stickpacks of acorresponding filling volume (adjustable through the width andespecially the length of the stickpacks) to produce different doses ofcalcium and magnesium in the following portions, each in a 2:1 ratio(Ca:Mg):

Filling amount of Calcium dose Magnesium dose stickpacks  50 mg  25 mg 591 mg 100 mg  50 mg 1182 mg 150 mg  75 mg 1773 mg 200 mg 100 mg 2364mg 250 mg 125 mg 2955 mg 300 mg 150 mg 3545 mg 350 mg 175 mg 4136 mg

Example 10

The finished mixture from Example 4 can be used to produce differentcalcium doses with different dosing ratios of calcium to magnesium. Thisyields the following filling quantities in stickpacks of a correspondingfilling volume (adjustable through the width and especially the lengthof the stickpacks):

Corresponding Corresponding weight of the weight of mixture frommagnesium Example 4 to be carbonate DC90 Filling used per S/C to be usedamount of Magnesium stickpack for for magnesium the Ca:Mg ratio Calciumdose dose calcium per stickpack stickpacks 4:1 100 mg  25 mg  778 mg  28mg  806 mg 2:1 100 mg  50 mg  778 mg  56 mg  834 mg 1:1 100 mg 100 mg 778 mg 111 mg  889 mg 3:1 150 mg  50 mg 1168 mg  56 mg 1224 mg 2:1 150mg  75 mg 1168 mg  83 mg 1251 mg 1.5:1   150 mg 100 mg 1168 mg 111 mg1279 mg 4:1 200 mg  50 mg 1557 mg  56 mg 1613 mg 2:1 200 mg 100 mg 1557mg 111 mg 1668 mg 1.33:1   200 mg 150 mg 1557 mg 167 mg 1724 mg 1:1 200mg 200 mg 1557 mg 222 mg 1779 mg 5:1 250 mg  50 mg 1946 mg  56 mg 2002mg 2.5:1   250 mg 100 mg 1946 mg 111 mg 2057 mg 2:1 250 mg 125 mg 1946mg 139 mg 2085 mg 1.67:1   250 mg 150 mg 1946 mg 167 mg 2113 mg 1:1 250mg 250 mg 1946 mg 278 mg 2224 mg 3:1 300 mg 100 mg 2335 mg 111 mg 2446mg 2:1 300 mg 150 mg 2335 mg 167 mg 2502 mg 1.5:1   300 mg 200 mg 2335mg 222 mg 2557 mg 1:1 300 mg 300 mg 2335 mg 333 mg 2668 mg

Example 11

A granular preparation with 167 mg calcium per dose can also be preparedby the following method:

Calcium acetate with a taste-masking coating:

Calcium acetate (according to the 1980 g  requirements of the EuropeanPharmacopoeia), granulated (Paul Lohmann) Basic butylated methacrylatecopolymer, Ph. 400 g Eur. (Eudragit EPO ®, Evonik) Sodium dodecylsulfate  40 g Stearic acid  60 g Talc 160 g

Other ingredients:

Aspartame  30 g Sorbitol 600 g Xylitol 320 g Orange flavoring 100 gFinished effervescent granules 810 g from Example 2

First, a film coating suspension with an excess of 25% is added to theingredients of the coating material as listed above. The excess coversthe spray losses during production so that the planned quantity of acoating of 20% methacrylate polymer can be applied. To do so, first 50 gsodium dodecyl sulfate is dissolved in 3.5 L of purified water at roomtemperature (approximately 20° C.). After 5 minutes, 75 g stearic acidis dispersed in the solution while stirring further using anUltraTurrax. After another 5 minutes, 500 g Eudragit EPO is distributedin the dispersion while stirring further and is further dispersed for 30minutes intensely using the UltraTurrax. In parallel, 200 g talc isdispersed in 1.5 L purified water at room temperature (approximately 20°C.) while stirring with an UltraTurrax and then stirring is continuedintensely for 20 minutes more. The two dispersions are mixed togetherand then applied to the granulated calcium acetate by means of afluidized bed device with a Wurster insert (Glatt GCPG2 LabSystem) inthe bottom spray method. The dispersions are applied in two partialbatches, each using half of the materials. The inlet air temperature isset at approximately 50° C., so that a product temperature ofapproximately 30° C. is established during film coating. The suspensionis applied to the calcium acetate through a 1.2 mm nozzle at an airpressure of approximately 1.5 bar and at a feed rate of 10 g per minute.The process is terminated when the weight of the granules has increasedby approximately 33%. The coated granules from the two partial batchesis passed through a 2 mm screen and mixed with the other ingredients ina 10 liter cube mixer and then welded in aluminum stickpacks in portionsof 1500 mg each.

Example 12

A granular preparation with 110 mg calcium and 60 mg magnesium per dosecan be prepared by the following method:

Calcium acetate from Example 11 with a taste- 1740 g  masking coating(calcium acetate content 75%) Heavy magnesium carbonate (according tothe 785 g requirement of the European Pharmacopoeia), granulated withapproximately 10% cornstarch (magnesium carbonate DC90 S/C Paul Lohmann)Aspartame  30 g Sorbitol 600 g Xylitol 400 g Orange flavoring 100 gFinished effervescent granules from Example 2 695 g

All the ingredients are mixed in a 10-liter cube mixer and welded inaluminum stickpacks in portions of 1450 mg each.

Example 13

A granular preparation with 220 mg calcium and 120 mg magnesium per dosecan be packaged in aluminum stickpacks by filling the finished mixturefrom Example 12 into aluminum stickpacks in portions of 2900 mg each.

Example 14

A preparation containing 125 mg lanthanum (=238.5 mg lanthanumhydroxycarbonate) per dose can be prepared by the following method:

Lanthanum hydroxycarbonate 715 g (lanthanum content 52.4%) Aspartame  10g Sorbitol 200 g Xylitol 100 g Orange flavoring  30 g Finishedeffervescent granules 220 g from Example 2

All the ingredients are mixed in a 5-liter cube mixer. The mixture iswelded in an aluminum stickpack in portions of 425 mg each.

Example 15

Preparations containing 250 mg, 500 mg, 750 mg and 1000 mg lanthanum perdose can be obtained by filling the mixture from Example 14 intoaluminum stickpacks according to the following table:

Corresponding Filling amount of weight of stickpacks with lanthanumfinished mixture Lanthanum dose hydroxycarbonate from Example 14 250 mg 477 mg  850 mg 500 mg  954 mg 1700 mg 750 mg 1431 mg 2550 mg 1000 mg 1908 mg 3400 mg

Example 16

A preparation with 800 mg sevelamer hydrochloride per dose can beprepared by the following method:

Sevelamer hydrochloride, dried 800 g Aspartame  10 g Sorbitol 200 gXylitol 100 g Orange flavoring  40 g Finished effervescent granules 250g from Example 2

All the ingredients are mixed in a 5-liter cube mixer. The mixture iswelded in an aluminum stickpack in portions of 1400 mg each.

Example 17

Preparations with 1600 mg and 2400 mg sevelamer per dose can be packagedin aluminum stickpacks by filling the mixture from Example 16 intoaluminum stickpacks according to the following table:

Filling amount of Sevelamer stickpacks with finished dose mixture fromExample 16 1600 mg 2800 mg 2400 mg 4200 mg

Example 18

A preparation with 800 mg sevelamer hydrochloride per dose can beprepared by the following method:

Sevelamer hydrochloride, dried 800 g Povidone K30  50 g Aspartame  10 gSorbitol 200 g Xylitol 100 g Orange flavoring  40 g Finishedeffervescent granules 250 g from Example 2

Povidone K30 is dissolved in 150 mL of a mixture of 90% ethanol and 10%purified water. Sevelamer hydrochloride is granulated with the povidonesolution in a fluidized bed granulator (Glatt GCPG2 LabSystem) in thetop spray method. The granules are passed through a 1 mm screen andmixed with the other ingredients in a 5-liter cube mixer. The mixture iswelded in an aluminum stickpack in portions of 1450 mg each.

1. A pharmaceutical composition in the form of pourable granules or achewable tablet containing at least one phosphate binding substance andat least one effervescent agent which contains a carbonate and a solidorganic edible acid or the acidic salt thereof for use in treatment ofrenally insufficient patients, where the composition is administeredorally without adding water.
 2. The composition according to claim 1,characterized in that the carbonate is an alkali or alkaline earthcarbonate or an alkali or alkaline earth bicarbonate.
 3. The compositionaccording to claim 1, characterized in that the phosphate-bindingsubstance is a calcium salt, a magnesium salt, an ion exchanger polymer,a lanthanum compound or an iron compound.
 4. The composition accordingto claim 1, characterized in that the phosphate binding substance iscalcium acetate.
 5. The composition according to claim 1, characterizedin that the phosphate-binding substance is present in granulated form.6. The composition according to claim 1, characterized in that thephosphate binding substance is provided with a taste-masking coating. 7.The composition according to claim 6, characterized in that the coatingis prepared by a spray coating method in a fluidized bed.
 8. Thecomposition according to claim 7, characterized in that the coating is amelt coating.
 9. The composition according to claim 7, characterized inthat the coating is a spray coating of suspensions and/or solutions. 10.The composition according to claim 1, characterized in that thecomposition contains magnesium carbonate.
 11. The composition accordingto claim 1, characterized in that the effervescent agent is contained ina coating of the phosphate-binding substance.
 12. The compositionaccording to claim 1, characterized in that it contains at least onesugar alcohol.
 13. The composition according to claim 1, characterizedin that the phosphate-binding substance constitutes 15-80% of the weightof the composition.
 14. The composition according to claim 1,characterized in that the effervescent agent constitutes 3-60% of theweight of the composition.
 15. The composition according to claim 1,characterized in that the oral cavity is rerinsed with water after oraladministration of the composition.
 16. The composition according toclaim 1, characterized in that it is taken in a dose of 0.5-5 g three orfour times daily, preferably with meals.
 17. The composition accordingto claim 1, characterized in that the average particle size of thegranules is 100-3500 μm.
 18. A stickpack containing 0.5-4 g of acomposition according to claim
 1. 19. A pharmaceutical composition inthe form of untableted granules containing at least one effervescentagent and containing calcium acetate and magnesium carbonate in a weightratio of 1:1 to 4:1.